Aleutian mink disease parvovirus (ADV) causes a persistent infection that is restricted in adult animals and is associated with disturbances of immune regulation. Features of Aleutian disease (AD) include polyclonal hypergammaglobulinemia, plasmacytosis, immune complex disease, interstitial and glomerulonephritis and exceedingly high levels of anti- ADV antibodies. The spectrum of findings resembles those associated with a Th2 pattern of cytokine responses. The scope of this project is to elucidate mechanisms by which ADV infection results in this unusual disorder. We found that levels of the cytokine Interleukin-6 (IL-6) increased as mink infected with ADV develop disease. Furthermore, amounts of IL-6 mRNA also appeared to increase as mink developed AD. Conditions in which IL-6 is overexpressed in human and mice resemble the clinicopathologic picture of ADV infection in adult mink. Inappropriate production of IL- 6, and possibly other cytokines, during chronic ADV infection may play a role in the generation of the immune disorders. This would be consistent with a Th2 type of immune response. Analysis of transcription suggested that restricted ADV infection may be associated with reduced synthesis of either capsid proteins or nonstructural protein 2 (NS2). Disrupted NS2 synthesis has been found to cause nonpermissive infection for other parvoviruses in a cell type specific fashion. Infected mink do not generate a detectable antibody response against all regions of the various nonstructural (NS) proteins. When sera were tested against fusion proteins containing open reading frames specific for segments of the NS proteins, we found antibodies directed against NS1 specific regions and the amino-terminal region common to all NS proteins, but no reactivity against the NS2 specific ORF. An antibody prepared against the NS2 specific ORF detected a protein of the correct size indicating that NS2 is a bona fide gene product in permissively infected cells. Consequently, NS2 may not be expressed in vivo during ADV infection. This finding might implicate disordered NS2 synthesis in restricted in vivo infection.